Antiretroviral resistance during successful therapy of HIV type 1 infection

Abstract

HIV type 1 (HIV-1) drug resistance mutations were selected during antiretroviral therapy successfully suppressing plasma HIV-1 RNA to <50 copies/ml. New resistant mutant subpopulations were identified by clonal sequencing analyses of viruses cultured from blood cells. Drug susceptibility tests showed that biological clones of virus with the mutations acquired during successful therapy had increased resistance. Each of the five subjects with new resistant mutants had evidence of some residual virus replication during highly active antiretroviral therapy (HAART), based on transient episodes of plasma HIV-1 RNA > 50 copies/ml and virus env gene sequence changes. Each had received a suboptimal regimen before starting HAART. Antiretroviral-resistant HIV-1 can be selected from residual virus replication during HAART in the absence of sustained rebound of plasma HIV-1 RNA.

Figure 1

Plasma HIV-1 RNA levels and antiretroviral regimens for patients 9 (A), 23 (B), and 24 (C). () When viruses were analyzed. RNA assays with a lower detection limit of 50 (●) or 400 (○) copies/ml.

Figure 2

(A) Percentage of biological clones from patient 9 with at least one protease inhibitor resistance mutation. Solid lines indicate best fit (r² > 0.99). Extrapolation (dashed line) estimates proportion of virus population with ritonavir-selected mutations at HAART baseline. (B) Genetic variability of patient 9's biological clones in env C2-V3-C3, by using Jukes-Cantor (open bars) and Kimura measures (solid bars) (17). Each time point shown is based on at least eight clones. Second and third time points were each significantly less than the first (P < 0.05 and P < 0.001, respectively). The third time point was significantly less than the second (P < 0.001). The fifth time point had significantly greater env diversity than the third (P < 0.001), but was not significantly different from the first. The sixth time point was significantly less diverse than the fifth (P < 0.01). Statistical analyses were the same with each measure of genetic distance. Bars indicate standard error.

Figure 3

Non-synonymous to synonymous substitution ratios for C2-V3 region env and protease sequences from virus biological clones from patients 9 (○), 23 (□), and 24 (◊). Mean genetic distances and standard error are plotted. The number in each symbol represents the time point.